1. Field of the Invention
This invention relates to a fibril-preventing peptide and a method for preventing the formation of fibrils and more particularly, this invention relates to a peptide and a method for preventing the formation of solid protein structures and disease associated therewith.
2. Background of the Invention
“Conformational diseases,” share a common etiology whereby proteins fold irregularly to produce structural flaws. These flaws result in the proteins unnaturally aggregating and thereafter precipitating as fibrils from their solvents. Such solvents include blood, urine, water, lymph, cerebrospinal fluid, and other physiological fluids. Diseases such as sickle cell anemia, amyloid light chain disease, senile systemic amyloidosis, Alzheimer's, and prion encephalopathies including kuru and “mad cow” disease or BSE, are the result of protein conformation anomalies.
The immunoglobulin light chain (LC) is normally a soluble, secreted protein, but some light chains aggregate into ordered fibrils with characteristics similar to other amyloid deposits. Among the human immunoglobulin variable domain (VL) sequences known to form amyloid fibers, somatically mutated derivatives of a small number of germline genes are over-represented. One of these is kappa-IV, many of whose derivatives are associated with light chain amyloidosis. The tendency of kappa-IV sequences to form fibrils is inversely correlated with their thermodynamic stability, and while both stabilizing and destabilizing mutations are found in amyloidogenic kappa-IV sequences, only destabilizing mutations promote fibril formation.
The inventors have found that the conformational change required to convert a soluble light chain into a fibrillogenic variant can be caused by single somatic mutations. Importantly, an aggregating light chain can nucleate fibril formation of a soluble light chain when sufficient sequence compatibility exists. This has important implications in the context of ongoing hypermutations, whereby multiple light chain sequences are generated.
Fibril deposition and build-up in tissues is the underlying mechanism of a number of diseases for which no drug therapy currently exists. However, research has shown that flufenamic acid inhibits the conformational changes of transthyretin which is associated with amyloid fibril formation. S. A. Peterson et al. Proc. Natl. Acad. Sc. USA (Oct. 27, 1998) 95(22): 12956-60.
Once fibril build-up occurs, often the only intervention is surgical whereby the over-ladened tissue has to be modified or else removed.
A need exists in the art for a substance and process to stymie the in vivo precipitation of protein. The substance and process should incorporate physiologically compatible materials and require no invasive procedures common with more typical treatments of protein deposit diseases.